In innate immunity, Toll-like receptor (TLR) regulates proinflammatory cytokine outputs through recruitment of TIR-domain containing adaptor proteins. Recently, we identified SCIMP as a proximal, transmembrane adaptor for TLR phosphorylation and signalling outputs. SCIMP binds directly to the cytosolic TIR domain of TLR4 via an unusual TIR-non-TIR interaction1. Mechanistically, SCIMP scaffolds Lyn kinase for TLR phosphorylation to modulate downstream signalling and these results in the selective LPS-mediated secretion of IL-6 and IL-12p40 but not other cytokines. SCIMP itself is phosphorylated and using three recently developed molecular probes2 we show that three tyrosine residues in SCIMP (Y58, Y96, and Y120) are activated by LPS and by multiple other TLR ligands. In turn, this allows SCIMP to recruit distinct effector proteins Grb2, Csk, and/or SLP65 with divergent kinetics, varying TLR-mediated signalling outputs. In additional, our recent unpublished data revealed that SCIMP is a common adaptor, which binds to diverse TLRs for their signalling outputs. Our studies implicate SCIMP as a universal transmembrane adaptor for multiple TLR activation and reveal how SCIMP as a proximal adaptor can impart remarkable specificity to a range of TLR-driven inflammatory cytokine responses.
References:
1 Luo et al. Nat Commun, 2017, PMID 28098138
2 Luo et al. Immunol Cell Biol, 2017, PMID 28290451